Conformational analysis of the cholecystokinin C-terminal octapeptide: a nuclear magnetic resonance and computer-simulation approach

https://doi.org/10.1016/0167-4838(87)90006-9Get rights and content

Abstract

The C-terminal octapeptide portion of cholecystokinin (CCK8) has well-defined biological properties which include action as a neurotransmitter and induction of gall-bladder contraction and pancreatic enzyme secretion. Many analogues of CCK8 have been prepared and tested for potency, making this an ideal model system in which to initiate evaluation of structure-function relationships. The present study uses high-resolution proton nuclear magnetic resonance (NMR) spectroscopy and energy minimization techniques to evaluate the solution (DMSO) and in vacuo conformation(s) of CCK8. The NMR results provide amide and CαHα chemical shift temperature dependencies and all φ dihedral angles and χ1 rotamer populations. The energy minimization data located deep potential energy wells, for which all torsion angles are reported. Collectively, the data support models for CCK8 where the structures are characterized by a high degree of folding. These conformations are characterized by sharp turns, possibly stabilized by hydrogen-bonds. Taken together with pharmacologic data and somewhat similar folded structures implied from fragments of CCK8, it is suggested that both electrostatic and steric effects are needed for full biological potency.

References (50)

  • L. Sjodin et al.

    Gastroenterology

    (1977)
  • S.R. Peikin et al.

    J. Biol. Chem.

    (1979)
  • J.D. Gardner et al.

    Biochim. Biophys. Acta

    (1980)
  • M. Praissman et al.

    Biochim. Biophys. Acta

    (1982)
  • C. Durieux et al.

    Biochem. Biophys. Res. Commun.

    (1983)
  • D.J. States et al.

    J. Magn. Resonance

    (1982)
  • A. Bax et al.

    J. Magn. Resonance

    (1985)
  • R. Baumann et al.

    J. Magn. Resonance

    (1981)
  • K. Nagayama et al.

    Biochem. Biophys. Res. Commun.

    (1977)
  • G. Wider et al.

    J. Magn. Resonance

    (1981)
  • K. Nagayama et al.

    J. Magn. Resonance

    (1978)
  • A. Pardi et al.

    J. Mol. Biol.

    (1984)
  • J. Feeney

    J. Magn. Resonance

    (1976)
  • G.D. Rose et al.

    Adv. Protein Chem.

    (1985)
  • V. Mutt et al.

    Eur. J. Biochem.

    (1968)
  • V. Mutt et al.

    Biochem. J.

    (1971)
  • J.E. Jorpes et al.

    Acta Physiol. Scand.

    (1966)
  • G.J. Dockray

    Nature

    (1976)
  • J.F. Rehfeld et al.
  • M.A. Ondetti et al.

    Am. J. Digest. Dis.

    (1970)
  • M. Bodanszky et al.

    Int. J. Peptide Protein Res.

    (1980)
  • M. Spanarkel et al.

    J. Biol. Chem.

    (1983)
  • C. Briet et al.

    Int. J. Peptide Protein Res.

    (1985)
  • P. Pham Van Chuong et al.
  • Cited by (23)

    • Conformational and molecular modeling studies of sulfated cholecystokinin-15

      2002, Biochemical and Biophysical Research Communications
    • Models for the A- and B-Receptor-Bound Conformations of CCK-8

      1993, Biochemical and Biophysical Research Communications
    View all citing articles on Scopus
    View full text